CRISPR corrects clustered DMD mutations

Using CRISPR-Cas 9 genome editing, US and German stem cell researchers have corrected clustered mutations in the dystrophin gene in heart mucle cells obtained from induced pluripotent stem cells of patients with Duchenne muscular dystrophy (DMD).

Through the technique, they were able to improve both muscle and cardiac abnormalities associated with DMD, they report in Science Advances. According to the authors from University of Texas, Dallas, and the German Center for Cardiovascular Research in Göttingen, their approach might salvage muscle function in up to 60% of DMD patients.

Degenerative muscle disease Duchenne muscular dystrophy is caused by large deletions, large duplications and point mutations in the X-linked dystrophin gene (DMD). Given the thousands of individual mutations that have been identified in humans with the disease, how such a large number of mutations might be corrected by CRISPR/Cas9 genome editing has been a lingering question.

Studies of the DMD gene to date have pinpointed clustered mutations responsible for DMD abnormalities in “hot spot” areas. Eric Olson, Wolfram-Hubertus Zimmermann and colleagues proposed a method that allows the removal of a wide range of mutations in these regions, an approach they call „myoediting.”

Using CRISPR/Cas9 with single-guide RNAs, the researchers performed myoediting in heart muscle cells derived from induced pluripotent stem cells from people with various types of mutations within the DMD gene. They efficiently restored expression of the dystrophin protein in these cardiac muscle cells. The researchers believe that, while their findings hold promise for effectively correcting muscle and cardiac mutations associated with DMD, futures studies of possible off-target effects are necessary before potential therapeutic action.

At the beginning of January, however, results from Stanford researchers hit a blow to the hype around CRISPR-based therapies, the first of which will undergo clinical testing this year. In an e-paper published prior to peer review on the preprint portal bioRxiv, Matthew Porteus’ group outlined that they found antibodies against the most common forms of the bacterial restriction enzyme CAS9, which cuts the DNA at locations defined by CRISPR binding. While Porteus suggested there might be ways around immunity against CRISPR, which would affect genome editing efficacy, they found antibodiess against staphylococcal CAS9 in 79% of human volunteers’ blood serum and against 65% of streptococcal CAS9 endonuclease. What’s more, they found antigen-specific T cells in almost half (46%) of the blood donors. They say, that’s because CRISPR actually comes from bacteria that often infect human.

However, Porteus’ findings may be not relevant for current an ex vivo genome therapies coming to the clinic this year: In December, Vertex Pharmaceuticals and ist development partner CRISPR Therapeutics announced they have filed for conducting clinical Phase I tests in Europe with its CRISPR-based therapy, CTX001, to correct β-thalassemia. At JP Morgan conference, CRISPR Therapeutics competitor Editas Medicine announced it will submit an IND for the company’s Leber Congenital Amaurosis type 10 programme EDIT-101 in mid-2018. LCA10 is a subtype of the most common cause of inherited childhood blindness for which currently the first treatment approaches are in clinically testing. It makes up 20-20% of all LCA cases and is caused by mutations in the CEP290 gene. The drug will act locally and is for direct injection into the eye.

The Amsterdam-based company said it will primarily use the proceeds to advance its lead product XC001, licenced from Weill Cornell Medicine, to...

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